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Improved preparation method for cinepazide maleate

A technology of cinepazide maleate and piperazine, which is applied in the field of preparation of cinepazide maleate to achieve the effects of mild reaction conditions, less by-products and reduced energy consumption

Inactive Publication Date: 2009-08-19
DALIAN UNIV OF TECH +1
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0019] The technical problem to be solved in the present invention is to improve the preparation method of cinepazide maleate, which is embodied in: (1) when preparing 1-[(1-tetrahydropyrrolecarbonyl) methyl] piperazine (II), Reduce the amount of piperazine, adopt milder reaction conditions, to reduce the generation of double-substituted piperazine by-products, avoid using multiple vacuum decompression distillation or steam distillation in the aftertreatment process simultaneously; (2) in the preparation of cinnamon In the case of pazide free base (III), a solvent with low toxicity and good safety is used to simplify post-processing operations and improve product quality; a preparation method for cinepazide maleate suitable for industrial scale production is provided

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 1) Preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0057] Reaction formula:

[0058]

[0059] At room temperature, add 11.7g (0.136mol) of anhydrous piperazine and 6.3g (0.045mol) of anhydrous potassium carbonate into 100ml of absolute ethanol and stir evenly. Then slowly add a solution of 6.6g (0.045mol) chloroacetylpyrrolidine and 30ml of absolute ethanol dropwise; keep warm for 3 to 4 hours (GC or TLC to follow the reaction process: methanol is the developer, iodine, chloroacetylpyrrolidine R f = 0.7, 1-piperazine acetylpyrrolidine R f =0.4), remove the solid residue by suction filtration, use 20ml acetone to stir at room temperature after 10min ice-water bath cooling after the obtained filtrate spins to dryness, remove the white powder (being piperazine, recycling) by suction filtration, after the filtrate spins to dryness Vacuum drying gave 8.4 g of a yellowish white solid with a yield of 95.6% and a GC purity of ≥99%.

[0060] 1 H-NMR (DM...

Embodiment 2

[0077] 1) Preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0078] Reaction formula:

[0079]

[0080] At room temperature, add 15.6g (0.181mol) of anhydrous piperazine into 100ml of absolute ethanol and stir evenly. Then slowly add a solution of 6.6g (0.045mol) chloroacetylpyrrolidine and 30ml of absolute ethanol dropwise; keep warm for 3 to 4 hours (GC or TLC to follow the reaction process: methanol is the developer, iodine, chloroacetylpyrrolidine R f = 0.7, 1-piperazine acetylpyrrolidine R f=0.4); after the reaction solution was evaporating to dryness, stir it with 20ml acetone at room temperature for 10min and then cool it in an ice-water bath, remove the white powder (being piperazine, recycle) by suction filtration, and vacuum-dry the filtrate to obtain a yellowish white color after evaporating to dryness. The solid is 8.8g, the yield is 100%, and the GC purity is 90.3%.

[0081] 1 H-NMR (DMSO-d 6 ): δ 1.747 (m, 2H, pyrrolidine-CH 2 -), δ 1.829...

Embodiment 3

[0098] 1) Preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0099] Reaction formula:

[0100]

[0101] At room temperature, 11.7g (0.136mol) of anhydrous piperazine and 6.3g (0.045mol) of anhydrous potassium carbonate were added to 100ml of absolute ethanol and stirred evenly. Then slowly add a solution of 6.6g (0.045mol) chloroacetylpyrrolidine and 30ml of absolute ethanol dropwise; keep warm for 3 to 4 hours (GC or TLC to follow the reaction process: methanol is the developer, iodine, chloroacetylpyrrolidine R f = 0.7, 1-piperazine acetylpyrrolidine R f =0.4), remove the solid residue by suction filtration, use 20ml acetone to stir at room temperature after 10min ice-water bath cooling after the obtained filtrate spins to dryness, remove the white powder (being piperazine, recycling) by suction filtration, after the filtrate spins to dryness Vacuum drying gave 8.4 g of a yellowish white solid with a yield of 95.6% and a GC purity of ≤99%.

[0102] 1 H...

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Abstract

An improved preparation method of cinepazide maleate belongs to the pharmaceutical technical field. The improved preparation method is characterized in that anhydrous piperazine reacts with chloracetylpyrrolidine in absolute ethyl alcohol at room temperature to obtain 1-[(1-tetrahydropyrrolylcarbonyl)methyl]piperazine, post-treatment method is a acetone dissolution and filtration method; then the 1-[(1-tetrahydropyrrolylcarbonyl)methyl]piperazine reacts with 3,4,5-trimethoxycinnamoyl chloride at the room temperature to obtain cinepazide free alkali, an acid-binding agent used is triethylamine, and a solvent is selected from acetone or tetrahydrofuran, methyl ethyl ketone, methylbenzene, xylene, methyl isobutyl ketone, cyclohexanone and the like, and the acetone is preferred; finally, the cinepazide maleate is obtained after salifying with maleic acid. The improved preparation method has the effects and benefits of using a cheap and low-toxic solvent with good safety in the process of preparing the cinepazide maleate (I), mild reaction conditions, simple operation, fewer by-products, low energy consumption and equipment requirements, higher product yield and good product quality, and being suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of cinepazide maleate, which belongs to the technical field of medicine. Background technique [0002] The chemical name of cinepazide maleate is: trans-1-[(pyrrolidinecarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine maleate; English name: Cinepazide Maleate, its molecular formula is C 26 h 35 N 3 o 2 , the chemical structural formula (I) is as follows: [0003] [0004] Cinepazide maleate is a calcium ion channel blocker, by blocking Ca 2+ Transmembrane into vascular smooth muscle cells, relax vascular smooth muscle, dilate cerebral blood vessels, coronary blood vessels and peripheral blood vessels, thereby relieving vasospasm, reducing vascular resistance, and increasing blood flow. Can enhance the effect of adenosine and cyclic adenosine monophosphate (cAMP), reduce oxygen consumption. This product can inhibit cAMP phosphodiesterase and increase the amount of cAMP. It can also improve ...

Claims

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Application Information

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IPC IPC(8): C07D295/185A61P9/00A61P9/10A61P7/02
Inventor 孟庆伟刘华祥都健张成海陈祥麟于翔董述祥郝雅男
Owner DALIAN UNIV OF TECH
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